THrombolysis for Acute Wake-up and Unclear-onset Strokes With Alteplase at 0.6 mg/kg Trial (THAWS)

Phase 3

Conditions: Stroke

Interventions: Other: Standard care
Drug: Tissue-type plasminogen activator (alteplase)

Registration Number: NCT02002325

Lead Sponsor: National Cerebral and Cardiovascular Center, Japan

Brief Summary: The purpose of this study is to clarify efficacy and safety of MRI-based intravenous thrombolysis with alteplase for patients with acute wake-up ischemic stroke and those having acute ischemic stroke with unknown time of symptom onset.

Detailed Description: THAWS is an investigator initiated Japanese multicenter randomized controlled clinical trial of MRI based thrombolysis in patients with acute wake-up ischemic stroke and those having acute ischemic stroke with unknown time of symptom onset. Intravenous thrombolysis with alteplase of 0.6mg/kg, different from 0.9mg/kg used in other countries, is available as effective and safe treatment of acute stroke within 4.5 hours of symptom onset in Japan. However, time of symptom onset is unknown in about 25% of acute stroke patients. These patients are currently excluded from intravenous thrombolysis with alteplase. The objective of the THAWS project is to provide effective treatment options for acute stroke patients with unknown time of symptom onset. The purpose of this study is to clarify efficacy and safety of MRI-based intravenous thrombolysis with alteplase of 0.6mg/kg for patients with acute wake-up ischemic stroke and those having acute ischemic stroke with unknown time of symptom onset. Eligible patients will be selected based on MRI findings indicative of acute ischemic stroke less than 4.5 hours of age.

Recruitment & Eligibility

Status: UNKNOWN

Sex: All

Target Recruitment: 300

Inclusion Criteria

Clinical diagnosis of acute ischemic stroke with unknown symptom onset (e.g. acute wake-up ischemic stroke, acute ischemic stroke with unknown time of symptom onset)
Last known well without neurological symptoms >4.5 hours of treatment initiation
Treatment can be started within 4.5 hours of symptom recognition (e.g. awaking)
Acute stroke MRI including diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) completed
Alberta Stroke Program Early CT score (ASPECTS) on initial DWI is 5 or more
No marked parenchymal hyperintensity visible on FLAIR
Initial NIHSS ≥2
Written informed consent by patient or next of kin

Exclusion Criteria

Pre-stroke Modified Rankin Scale (mRS) >1 (patients who have inability to carry out all daily activities and require some help or supervision)
Contraindications in the Japanese guideline for the intravenous application of recombinant tissue-type plasminogen activator (alteplase)
- History of nontraumatic intracranial hemorrhage
- History of stroke within the last 1 month (excluding transient ischemic attack)
- History of significant head/spinal injury or surgery within the last 3 months
- History of gastrointestinal or urinary tract bleeding within the last 21 days
- History of major surgery or significant trauma other than head injury within the last 14 days
- Hypersensitivity to alteplase
- Suspected subarachnoid hemorrhage
- Concurrent acute aortic dissection
- Concurrent hemorrhage (e.g., intracranial, gastrointestinal, urinary tract, or retroperitoneal, hemoptysis)
- Systolic blood pressure ≥185 mmHg despite antihypertensive therapy
- Diastolic blood pressure ≥110 mmhg despite antihypertensive therapy
- Significant hepatic disorder
- Acute pancreatitis
- Blood glucose <50mg/dL or >400 mg/dL
- Platelet count ≤100,000/mm3
- International normalized ratio of prothrombin time (PT-INR) >1.7 or Prolonged activated partial thromboplastin time (aPTT: >1.5 times the baseline value [>approximately 40 seconds only as a guide]) for patients on anticoagulation therapy or those with abnormal coagulation
Any contraindication to MRI (e.g. cardiac pacemaker)
Extensive early ischemic change in brain stem or cerebellum (e.g., more than half of brain stem or more than one hemisphere of cerebellum)
Planned or anticipated treatment with surgery or endovascular reperfusion strategies (e.g., intra-arterial thrombolysis, mechanical recanalization techniques)
Pregnant, lactating, or potentially pregnant
Life expectancy 6 months or less by judgment of the investigator
Inappropriate for study enrollment by judgment of the investigator

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard Care	Standard care	Standard treatment for acute stroke
Alteplase	Tissue-type plasminogen activator (alteplase)	Intravenous tissue-type plasminogen activator (alteplase)

Primary Outcome Measures

Name	Time	Method
Modified Rankin Scale 0-1	90 days after stroke onset

Secondary Outcome Measures

Name	Time	Method
Infarct volume growth	7 days after stroke onset	Infarct volume on FLAIR at 7 days minus infarct volume on DWI at baseline
Major bleeding	Up to 90 days after stroke onset	Fatal bleeding, symptomatic bleeding in a critical area or organ, such as intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, or bleeding causing a fall in hemoglobin level of ≥2g/dL, or leading to transfusion of ≥4.5 units of whole blood or red cells according to the definition of the International Society on Thrombosis and Haemostasis
Categorical shift in NIHSS score at 7 days	7 days after the initiation of treatment
Modified Rankin Scale 0-2	90 days after stroke onset
Categorical shift in modified Rankin Scale score	90 days after stroke onset
Parenchymal hemorrhage type-2 (PH-2)	24 hours after the initiation of treatment	MRI proven SICH
Symptomatic intracranial hemorrhage (sICH) in SITS-MOST	24 hours after the initiation of treatment	MRI proven SICH
Modified Rankin Scale 6	90 days after stroke onset	Death due to any cause
Categorical shift in National Institutes of Health (NIHSS) score at 24 h	24 hours after the initiation of treatment
sICH as defined in European Cooperative Acute Stroke Study (ECASS) II	24 hours after the initiation of treatment	MRI proven SICH
sICH as defined in National Institute of Neurological Disorders and Stroke (NINDS)	24 hours after the initiation of treatment	MRI proven SICH
Infarct volume	7 days after stroke onset	Infarct volume on FLAIR

Trial Locations

Locations (1): National Cerebral and Cardiovascular Center
🇯🇵
Suita, Osaka, Japan